Sleep Deprivation Cytokine and Neuroendocrine Effects on Perception of Effort

Cullen T Thomas G amp Wadley A J

Published PDF deposited in Coventry Universityrsquos Repository

Original citation Cullen T Thomas G amp Wadley AJ 2019 Sleep Deprivation Cytokine and Neuroendocrine Effects on Perception of Effort Medicine and Science in Sports and Exercise vol (In-press) pp (In-press) httpsdxdoiorg101249MSS0000000000002207

DOI 101249MSS0000000000002207 ISSN 0195-9131 ESSN 1530-0315

Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American College of Sports Medicine This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 40 (CCBY-NC-ND) where it is permissible to download and share the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy and Moral Rights are retained by the author(s) and or other copyright owners A copy can be downloaded for personal non-commercial research or study without prior permission or charge This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s) The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders

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Sleep Deprivation Cytokine and Neuroendocrine Effects on Perception of Effort

TOM CULLEN12 GAVIN THOMAS2 and ALEX J WADLEY34

1Centre for Sport Exercise and Life Sciences Coventry University Priory Street Coventry UNITED KINGDOM 2School of Sport and Exercise Science University of Worcester Henwick Grove Worcester UNITED KINGDOM 3National Centre for Sport and Exercise Medicine School of Sport Exercise and Health Sciences Loughborough University Loughborough UNITED KINGDOM and 4University Hospitals of Leicester NHS Trust Infirmary Square Leicester UNITED KINGDOM

ABSTRACT

CULLEN T G THOMAS and A J WADLEY Sleep Deprivation Cytokine and Neuroendocrine Effects on Perception of Effort Med Sci Sports Exerc Vol 52 No 4 pp 909ndash918 2020 Introduction An increased perception of effort and subjective fatigue are thought to be central to decreased exercise performance observed after disrupted sleep However there is limited understanding of mechanisms that under-pin these phenomena We investigated the role of interleukin-6 (IL-6) the soluble IL-6 receptor and neuroendocrine factors (cortisol adren-aline noradrenaline and brain-derived neurotropic factor) in mediating these responses at rest and during exercise Methods In a randomized order 10 healthy active men completed three experimental trials following different sleep conditions a single night of sleep deprivation par-tial sleep deprivation equivalent to 4 h of sleep and normal sleep The experimental sessions consisted of physiological and perceptual mea-

surements of exercise intensity throughout 45-min moderate intensity and 15-min maximal effort cycling Cytokine and neuroendocrine factors were assessed at rest and in response to exercise Results Sleep deprivation resulted in increased resting IL-6 lower blood glucose increased perceived fatigue and perception of effort lower free-living energy expenditure and reduced maximal exercise performance In con-trast sleep deprivation did not alter physiological cytokine or neuroendocrine responses to exercise Variations in the resting concentration of IL-6 were associated with lowered blood glucose an increased perception of effort and impaired exercise performance Resting concentrations of cortisol adrenaline noradrenaline and BNDF showed subtle interactions with specific aspects of mood status and performance but were not affected by sleep deprivation There were minimal effects of partial sleep deprivation Conclusions These findings demonstrate that cytokine and neuroendocrine responses to exercise are not altered by sleep deprivation but that changes in the resting concentration of IL-6 may play a role in altered perception of effort in this context Key Words SLEEP DEPRIVATION FATIGUE MOOD EXERCISE BDNF IL-6

It is widely recognized that poor sleep can have a negative ef- biological mechanisms involved in these phenomena remain fect on a wide array of psychological and physiological func- poorly understood An improved understanding of the mecha-tions (1) Numerous studies have also investigated the effect nisms involved in these processes may lead to improved manage-

of acute sleep deprivation on physical performance and although ment of or countermeasures to the negative effects of poor sleep there is a broad consensus that physiological responses to exer- There is a growing interest in the role of cytokines and neu-cise remain largely unchanged an elevation in RPE is thought roendocrine signaling factors (eg cortisol adrenaline nor-be a crucial factor mediating impaired exercise performance (2) adrenaline and brain-derived neurotropic factor (BDNF)) Interestingly there is evidence that increased perception of task and their relationship to changes in mood and sensation of fa-difficulty is a major factor in impaired performance of not only tigue (5) Mechanistic studies are often difficult in humans yet physical (3) but also cognitive tasks (4) and yet the underpinning there is good evidence that at least some of these signaling fac-

tors can readily cross the bloodndashbrain barrier and that even a small change in the circulating concentration can have signal-Address for correspondence Tom Cullen PhD Centre for Sport Exercise

and Life Sciences Coventry University Priory Street Coventry CV1 5FB ing effects within the brain (6) Indeed recent evidence sug-United Kingdom E-mail ad0189coventryacuk gests that the circulating concentration of BDNF is positively Submitted for publication July 2019 related to mood and cognition (7) whereas a negative relation-Accepted for publication October 2019 ship has been observed between interleukin-6 (IL-6) and mood 0195-9131205204-09090 (8) This is particularly important given that impaired mood MEDICINE amp SCIENCE IN SPORTS amp EXERCISEreg status and well-being are some of the most consistently re-Copyright copy 2019 The Author(s) Published by Wolters Kluwer Health Inc ported psychological effects of sleep deprivation (910) and on behalf of the American College of Sports Medicine This is an open-access

it is plausible that impairments in athletic performance may article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 40 (CCBY-NC-ND) where it is permissible be mediated in part by alterations in mood brought about by to download and share the work provided it is properly cited The work cannot be changes in cytokine or neuroendocrine signaling changed in any way or used commercially without permission from the journal Recent evidence has also documented a relationship be-DOI 101249MSS0000000000002207 tween IL-6 and BDNF after disrupted sleep (1112) Reports

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of lower circulating concentrations of BDNF are primarily from epidemiological studies and could therefore be confounded by other factors (eg diet or levels of physical activity) (11) Pre-vious well-conducted studies have shown that sleep deprivation can cause an elevation in IL-6 in response to acute sleep depriva-tion (12) however there is a limited study of soluble IL-6 recep-tor (sIL-6R) in this context The effects of IL-6 on the brain likely extend beyond mood and may affect the sensation of fa-tigue which could have important consequences for exercise performance (13) This may be important considering that recent evidence suggests that some of the fatigue-inducing effects of IL-6 may be related to ldquotrans-signalingrdquo through sIL-6R (14) Our group recently provided novel evidence that aspects of

IL-6 ldquotrans-signalingrdquo through the sIL-6R were related to mea-sures of sleep mood and perception of fatigue in elite athletes during a prolonged training period (15) However this study only examined resting measures and was limited in terms of the breadth of the analysis In fact the majority of studies have focused on resting concentrations of cytokine and neuroendo-crine responses after sleep deprivation whereas there is consider-ably less research assessing partial sleep deprivation which may be more similar to what is experienced in the real world Further-more very few studies have investigated any potential divergent responses to exercise Therefore the aim of the current study was to (a) characterize the effects of partial and complete sleep depri-vation on selected cytokine and neuroendocrine responses both at rest and in response to exercise and (b) to investigate their rela-tionship with subjective fatigue and effort perception

METHODS

Before commencement of the study the University Health Sciences Research Ethics Committee granted ethical approval (project code SH16170020-R) for all methods and ensured that the study conformed to the Declaration of Helsinki All partici-pants gave written informed consent to participate in the study

Participants

Participants comprised 10 recreationally active men Their age height weight and maximal oxygen uptake were as fol-lows (mean plusmn SD) 27 plusmn 6 yr 182 plusmn 8 cm 88 plusmn 8 kg and 43 plusmn 7 mLmiddotkgminus1middotminminus1 As part of the screening procedures par-ticipants completed departmental health screening and physical activity questionnaires and the Pittsburgh Sleep Quality Index (16) To take part in the study participants needed to declare themselves free from injury and illness for a minimum of 2 wk before commencement of the study and be identified as having normal sleep pattern based on a Global Pittsburgh Sleep Quality Index score lt5 (16) Participants were required to not be taking any medication known to interfere with normal inflammatory re-sponses (eg nonsteroidal anti-inflammatory drugs etc)

Study Design

This study comprised a randomized repeated-measures cross-over design Participants completed preliminary testing to ascer-tain a measurement of aerobic fitness (maximal oxygen uptake

(V O2max)) and were provided with an actigraph (Actiheart Version 22 CamNTech Ltd Cambridge United Kingdom) which was worn throughout the study and used to assess sleep and activity patterns throughout Energy expenditure was cal-culated in the 24-h period before each test session the 12 h on the same day of each test session and the 24-h period the day after each test to assess activity patterns before and after each condition In these conditions energy expenditure was measured using an Actiheart which integrates accelerometer and heart rate (HR) data (17)

Participants also completed a sleep diary estimating the quality of their sleep on a 5-point scale and the time at which they went to sleep and awoke the day before each test session After at least a 3-d rest participants completed three further experimental trials with manipulated sleep routines in a ran-domized and counterbalanced order with a further 7 d between each subsequent experimental trial To account for the known effects of time of day on hypothalamicndashpituitaryndashadrenal axis sympathetic nervous system mood and inflammatory signal-ing experimental test sessions were completed at the same time of day on each occasion (between 700 and 900 AM) The experimental trials consisted of a control condition (CON) partial sleep deprivation (PART) and a night of no sleep (DEP) which was equivalent to 24 h of sleep deprivation Be-fore CON participants obtained a normal night sleep (7ndash9 h) in their own bed For PART and DEP participants arrived at the laboratory the evening before testing and remained under the supervision of the researchers until testing was com-pleted the following day For PART participants were allowed a 4-h sleep opportunity in a prepared bedroom commencing at their normal bedtime and were then awoken 4 h later Once awake participants remained under the supervision of the re-searchers at all times to ensure that participants remained awake throughout the trial Participants carried out sedentary activities such as watching films reading and talking to the re-searchers Throughout this period participants were permitted to drink water ad libitum but were instructed to abstain from food for 12 h before the commencement of each test session and to replicate their diet in between conditions

During each experimental trial (detailed hereinafter) partic-ipants initially completed questionnaires for the assessments of mood states and a sleep diary After a brief rest participants then completed an aerobic exercise bout comprising 45 min of standardized submaximal exercise immediately followed by 15-min self-paced maximal effort time trial where participants were encouraged to cycle as far as possible Blood samples were taken at rest at the end of the submaximal exercise im-mediately after the completion of maximal exercise and after 30 min of recovery Blood samples were then later used for the assessment of circulating concentrations of specific cytokines and immune-endocrine markers A schematic representation of the experimental testing is provided in Figure 1

Preliminary Testing

Participants completed an incremental exercise test on an electromagnetically braked cycle ergometer (Lode Excalibur

910 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

FIGURE 1mdashA schematic representation of the experimental trial

Groningen the Netherlands) Expired gases were continu-ously measured using an online gas analysis system (Cortex Biophysik Metalyzer Leipzig Germany) whereas HR was measured via a short-range telemetric HR monitor (RS400 Polar Electro Espoo Finland) The protocol consisted of 3-min stages starting at 100 W and increased incrementally by 30 W each stage until volitional exhaustion Participants were instructed to maintain a pedal cadence of 80 rpm through-out the test V O2max was recorded as the highest 30-s period of oxygen consumption Oxygen consumption values obtained throughout each participantrsquos test were used to plot a linear re-gression of power output versus oxygen consumption and the resultant equation was then used to determine standardized power outputs for subsequent test sessions After the maximal test participants were then familiarized with tests to be con-ducted in subsequent sessions

Experimental Procedures

Subjective fatigue and mood states Participants completed a modified and shortened version of the Profile of Mood States questionnaire (18) to assess their subjective level of fatigue and mood status Participants scored them-selves on a 1ndash5 scale in the following categories tense mis-erable angry lively fatigued and confused Before completing the questionnaire participants were provided with a full expla-nation of each question Questionnaires of this type have been shown to be reliable and valid for assessing fatigue in sporting contexts (19)

Aerobic exercise session The aerobic exercise session consisted of a 45-min of submaximal cycling at a constant power output equivalent to 60 of the individuals V O2max This was immediately proceeded by a 15-min maximal effort self-paced time trial whereby participants were instructed to cycle as far as possible in the given time This allowed for the comparison of physiological and biochemical responses to both standardized submaximal exercise and maximal exer-cise within the same experimental protocol Distance traveled was calculated and expressed as a percentage of the distance that individual achieved in the control condition Respiratory gases and HR were measured continuously throughout each trial and expressed as a percentage of individualrsquos maximum value measured during the maximal incremental test Every 5-min RPE (20) blood lactate and glucose were measured Lactate and glucose were measured using an automated bench-top analyzer (Biosen C-Line Clinic EKF-diagnostic GmbH

Barleben Germany) from capillary blood samples obtained in the final 30 s of each 5-min period

Blood Collection and Analysis

A cannula (Becton Dickson amp Company Oxford United Kingdom) was inserted into the antecubital vein of the arm Whole blood (10 mL per time point) samples were collected into K3EDTA vacutainers (Greiner Bio-one Frickenhausen Germany) at rest (PRE) in the final 3-min of the submaximal portion of the exercise trial (DUR) at cessation of the maximal exercise (POST) and 30 min into recovery (30 MIN) Samples were then centrifuged at 4degC 3000g for 10 min and the resul-tant plasma was separated into aliquots and stored at minus80degC until subsequent analysis Commercially available enzyme-linked immunosorbent assay kits (Biotechne Abingdon United Kingdom) were used to quantify the concentration of IL-6 sIL-6R cortisol BDF adrenaline and noradrenaline All samples were analyzed in duplicate and the manufac-turerrsquos instructions were adhered to at all times To produce concentrations that were within the dynamic range of each as-say plasma samples were diluted with a commercially avail-able diluent (DY997 RampD Systems Ltd) before analysis of sIL-6R (1100) cortisol BDNF adrenaline and noradrena-line (all 120) To minimize variation between assays all sam-ples from an individual participant were analyzed in the same assay In our hands the intra-assay coefficients of variation for these assays were as follows IL-6 41 plusmn 26 sIL-6R 21 plusmn 18 cortisol 64 plusmn 47 BDNF 32 plusmn 22 adrenaline 40 plusmn 25 and noradrenaline 40 plusmn 41 The concentration of each analyte was determined in relation to a four-parameter standard curve (GraphPad Prism San Diego CA) and were corrected for changes in plasma volume based on established criteria (21)

Statistical Analysis

The ShapirondashWilk test was used to test for normality in scale data For resting and summary data one-way repeated-measures ANOVAs or nonparametric Friedman test was used where appropriate A two-way repeated-measures ANOVA (sleep conditionndashtime) was used to assess the effect of sleep condition on the exercise-induced responses for IL-6 sIL-6R cortisol BDNF adrenaline and noradrenaline When data were nonnormally distributed log transformations were per-formed before analysis and the respective data were then back transformed for ease of presentation in figures When main

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SLEEP DEPRIVATION IL-6 AND INCREASED RPE Medicine amp Science in Sports amp Exercisereg 911

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effects were identified post hoc analysis was performed using simple pairwise comparisons with Bonferroni adjustment or Dunnrsquos test where appropriate Pearson correlation and Spearman rank were used to assess the relationship between parametric and nonparametric data respectively Effect sizes for main effects are presented as η2 Statistical analyses were undertaken using GraphPad Prism and SPSS (IBM SPSS Sta-tistics for Windows Version 250 IBM Corp Armonk NY) All data are presented as mean plusmn SD unless otherwise stated and statistical significance was set at P lt 005

RESULTS

Sleep and energy expenditure Participants reported sleeping significantly more (467 plusmn 42 min) for CON than PART (2175 plusmn 21 min) and DEP (0 plusmn 0) respectively (F = 6749 P lt 0001 η2 = 098) with participants falling asleep later before PART than CON (P = 0039 mean differ-ence 19 min 95 confidence interval (CI) 09 to minus38 min) Sleep quality was significantly better for CON (33 plusmn 08) than for PART (26 0 plusmn 07) and DEP (0 plusmn 0 F = 9835 P lt 0001 η2 = 092) There was no significant difference in total energy expenditure in the 24 h before the test (2533 kcal for CON vs 2542 kcal for PART vs 2761 kcal for CON P gt 005) Energy expenditure in the 12 h after the experimental trials showed a main effect of condition (F = 52 P = 0018 η2 = 039) and was significantly lower in DEP than in CON (mean differ-ences minus208 kcal 95 CI minus404 to minus13 kcal) and PART (mean difference minus200 kcal minus396 to minus5 kcal) but were not signif-icantly different in the 24-h period the day after each trial (2681 plusmn 361 kcal for CON 2697 plusmn 514 kcal for PART 2547 kcal for DEP)

Resting measurements The results of subjective fa-tigue and mood status after each of the sleep conditions are summarized in Table 1 Participants reported being signifi-cantly more miserable (P = 0006) and confused (P = 0019) after DEP than CON while also feeling less lively (P = 0019) Participants reported being significantly more fatigued after PART and DEP than CON (P = 0001)

There were no significant differences in the resting concen-tration of sIL-6R cortisol BDNF adrenaline or noradrena-line between CON PART and DEP There was a significant effect of condition on resting IL-6 (F = 56 P = 0012 η2 = 039) and blood glucose (F = 42 P = 0032 η2 = 031 Figs 2A B respectively) Post hoc testing revealed signifi-cantly higher IL-6 after DEP (095 plusmn 037 pgmiddotmLminus1) versus

TABLE 1 Comparisons of fatigue and mood state after the three different sleep conditions

CON PART DEP

Tense 07 plusmn 07 11 plusmn 09 11 plusmn 09 Miserable 00 plusmn 00 02 plusmn 04 11 plusmn 13 Angry 00 plusmn 00 00 plusmn 00 02 plusmn 06 Lively 19 plusmn 10 15 plusmn 07 06 plusmn 08 Fatigued 07 plusmn 05 20 plusmn 07 27 plusmn 15 Confused 01 plusmn 03 05 plusmn 07 13 plusmn 16

Sleep conditions comprised normal night of 7- to 9-h sleep (CON) a 4-h sleep opportunity at the start of the night (PART) and a single night of sleep deprivation (DEP) Significantly different from control (P lt 005)

FIGURE 2mdashResting concentration of IL-6 (A) and blood glucose (B) after three different sleep conditions Sleep conditions comprised normal night of 7- to 9-h sleep (CON) a 4-h sleep opportunity at the start of the night (PART) and a single night of sleep deprivation (DEP) C Correlation be-tween resting IL-6 and blood glucose Significantly different from CON

CON (062 plusmn 022 pgmiddotmLminus1 mean difference minus033 pgmiddotmLminus1 95 CI minus059 to 006 pgmiddotmLminus1) and a significant de-crease in blood glucose (42 plusmn 03 mmolmiddotLminus1 for DEP vs 46 plusmn 05 mmolmiddotLminus1 for CON mean difference 044 mmolmiddotLminus1 95 CI 001ndash088 mmolmiddotLminus1) Correlation analysis revealed

912 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

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effects were identified post hoc analysis was performed using simple pairwise comparisons with Bonferroni adjustment or Dunnrsquos test where appropriate Pearson correlation and Spearman rank were used to assess the relationship between parametric and nonparametric data respectively Effect sizes for main effects are presented as η2 Statistical analyses were undertaken using GraphPad Prism and SPSS (IBM SPSS Sta-tistics for Windows Version 250 IBM Corp Armonk NY) All data are presented as mean plusmn SD unless otherwise stated and statistical significance was set at P lt 005

RESULTS

Sleep and energy expenditure Participants reported sleeping significantly more (467 plusmn 42 min) for CON than PART (2175 plusmn 21 min) and DEP (0 plusmn 0) respectively (F = 6749 P lt 0001 η2 = 098) with participants falling asleep later before PART than CON (P = 0039 mean differ-ence 19 min 95 confidence interval (CI) 09 to minus38 min) Sleep quality was significantly better for CON (33 plusmn 08) than for PART (26 0 plusmn 07) and DEP (0 plusmn 0 F = 9835 P lt 0001 η2 = 092) There was no significant difference in total energy expenditure in the 24 h before the test (2533 kcal for CON vs 2542 kcal for PART vs 2761 kcal for CON P gt 005) Energy expenditure in the 12 h after the experimental trials showed a main effect of condition (F = 52 P = 0018 η2 = 039) and was significantly lower in DEP than in CON (mean differ-ences minus208 kcal 95 CI minus404 to minus13 kcal) and PART (mean difference minus200 kcal minus396 to minus5 kcal) but were not signif-icantly different in the 24-h period the day after each trial (2681 plusmn 361 kcal for CON 2697 plusmn 514 kcal for PART 2547 kcal for DEP)

Resting measurements The results of subjective fa-tigue and mood status after each of the sleep conditions are summarized in Table 1 Participants reported being signifi-cantly more miserable (P = 0006) and confused (P = 0019) after DEP than CON while also feeling less lively (P = 0019) Participants reported being significantly more fatigued after PART and DEP than CON (P = 0001)

There were no significant differences in the resting concen-tration of sIL-6R cortisol BDNF adrenaline or noradrena-line between CON PART and DEP There was a significant effect of condition on resting IL-6 (F = 56 P = 0012 η2 = 039) and blood glucose (F = 42 P = 0032 η2 = 031 Figs 2A B respectively) Post hoc testing revealed signifi-cantly higher IL-6 after DEP (095 plusmn 037 pgmiddotmLminus1) versus

TABLE 1 Comparisons of fatigue and mood state after the three different sleep conditions

CON PART DEP

Tense 07 plusmn 07 11 plusmn 09 11 plusmn 09 Miserable 00 plusmn 00 02 plusmn 04 11 plusmn 13 Angry 00 plusmn 00 00 plusmn 00 02 plusmn 06 Lively 19 plusmn 10 15 plusmn 07 06 plusmn 08 Fatigued 07 plusmn 05 20 plusmn 07 27 plusmn 15 Confused 01 plusmn 03 05 plusmn 07 13 plusmn 16

Sleep conditions comprised normal night of 7- to 9-h sleep (CON) a 4-h sleep opportunity at the start of the night (PART) and a single night of sleep deprivation (DEP) Significantly different from control (P lt 005)

FIGURE 2mdashResting concentration of IL-6 (A) and blood glucose (B) after three different sleep conditions Sleep conditions comprised normal night of 7- to 9-h sleep (CON) a 4-h sleep opportunity at the start of the night (PART) and a single night of sleep deprivation (DEP) C Correlation be-tween resting IL-6 and blood glucose Significantly different from CON

CON (062 plusmn 022 pgmiddotmLminus1 mean difference minus033 pgmiddotmLminus1 95 CI minus059 to 006 pgmiddotmLminus1) and a significant de-crease in blood glucose (42 plusmn 03 mmolmiddotLminus1 for DEP vs 46 plusmn 05 mmolmiddotLminus1 for CON mean difference 044 mmolmiddotLminus1 95 CI 001ndash088 mmolmiddotLminus1) Correlation analysis revealed

912 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

TABLE 2 Summary of physiological and perceptual responses to a 45-min submaximal constant load cycling exercise and a 15-min self-paced maximal effort time trial after three separate sleep conditions

Submaximal Exercise CON PART DEP

Mean V O2 Max 625 plusmn 58 618 plusmn 57 611 plusmn 44 Mean HR Max 739 plusmn 38 739 plusmn 38 725 plusmn 43 Mean RER 089 plusmn 003 088 plusmn 004 087 plusmn 003 Mean Lactate mmolmiddotLminus1 20 plusmn 07 19 plusmn 07 18 plusmn 06 Mean RPE AU 118 plusmn 16 126 plusmn 09 134 plusmn 19 Maximal exercise Mean V O2 Max 854 plusmn 65 834 plusmn 62 785 plusmn 114 Mean HR Max 932 plusmn 22 915 plusmn 18 877 plusmn 61 Mean RER 096 plusmn 002 095 plusmn 003 092 plusmn 005 Mean lactate mmolmiddotLminus1 54 plusmn 07 49 plusmn 11 43 plusmn 15 Mean RPE AU 181 plusmn 13 179 plusmn 09 185 plusmn 11

Significantly different from control (P lt 005)

a significant negative relationship between resting IL-6 and blood glucose (P = 002 r = minus044 95 CI minus07 to minus007 see Fig 2 for a summary) Subjective fatigue at rest was neg-atively correlated with the total energy expenditure in the 12 h after the exercise (P = 001 r = minus046 95 CI minus075 to minus004) Resting concentrations of IL-6 and sIL-6R were neg-atively related (P = 001 r = minus048 95 CI minus072 to minus012) Adrenaline was negatively related to subjective perception of fatigue at rest (P = 0027 r = minus043 95 CI minus07 to minus006) whereas noradrenaline was positively related to perceived ldquoten-sionrdquo (P = 0027 r = 049 95 CI 007ndash077) BDNF was neg-atively related to perceived rating of ldquomiserablenessrdquo (P = 002 r = minus046 95 CI minus072 to minus009) and positively related to per-ceived ldquolivelinessrdquo (P = 0025 r = 044 95 CI 006ndash071)

Physiological and perceptual responses to exer-cise Physiological and perceptual responses to exercise are summarized in Table 2 whereas Figure 3 provides a graphical demonstration of the differences between key physiological and perceptual responses to the different sleep conditions There were no significant differences between any of the phys-iological responses (mean oxygen uptake (V O2) HR RER or lactate) between the three experimental conditions during the 45-min constant load portion of the exercise whereas percep-tion of effort (as measured by mean RPE) was significantly higher in DEP (134 plusmn 19) than in CON (118 plusmn 16 P = 003)

Physiological responses to maximal exercise were signifi-cantly different between CON and DEP There was a main ef-fect of condition on mean V O2 (F = 33 P = 0038 η2 = 03) which was significantly higher after CON (854 plusmn 55) than DEP (785 plusmn 114 mean difference 77 95 CI 03ndash149) Similarly there was a main effect of condition on distance traveled (F = 41 P = 0026 η2 = 023) with sig-nificantly less distance traveled in DEP than in CON (mean difference 114 95 CI 12ndash216 Fig 3C) Mean RPE during submaximal exercise was positively related to sub-jective fatigue at rest (P lt 0001 r = 063 95 CI 033ndash081) and negatively related to the mean V O2 achieved during the maximal exercise (P = 003 r = minus039 95 CI minus066 to minus004) and distance traveled (P = 0006 r = minus049 95 CI minus072 to minus016) Subjective fatigue at rest was negatively re-lated to mean V O2 (P = 0003 r = minus056 95 CI minus077 to minus022) and the distance traveled during maximal exercise

FIGURE 3mdashThe mean oxygen uptake (A) and perception of effort (B) during a 45-min submaximal constant load cycling exercise and a 15-min self-paced maximal effort time trial after three experimental sleep conditions C Distance traveled in the 15-min self-paced maximal effort time trial (relative to the distance each person traveled in the control con-dition) A significant difference between CON and DEP

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SLEEP DEPRIVATION IL-6 AND INCREASED RPE Medicine amp Science in Sports amp Exercisereg 913

(P lt 0001 r = minus07 95 CI minus086 to minus044) In contrast dis-tance traveled during maximal exercise was positively related to feeling of ldquolivelinessrdquo at rest (P lt 0001 r = 066 95 CI 037ndash083)

There was a main effect of condition on mean HR (F = 50 P = 0014 η2 = 027) which was significantly higher after CON (932 plusmn 22) than DEP (877 plusmn 61 mean differ-ence 54 95 CI 09ndash98) There was a main effect of condition on mean RER (F = 61 P = 0009 η2 = 04) which was significantly higher after CON (854 plusmn 55) than DEP (785 plusmn 114 mean difference 77 95 CI 03ndash 149) There was a main effect of condition on mean blood lactate (F = 38 P = 0039 η2 = 03) which was signifi-cantly higher after CON (54 plusmn 07 mmolmiddotLminus1) than DEP (43 plusmn 15 mmolmiddotLminus1 mean difference 11 mmolmiddotLminus1 95 CI 005ndash21 mmolmiddotLminus1) In contrast to submaximal exer-cise there was no effect of condition on mean RPE during the maximal exercise

Cytokine and neuroendocrine responses to exer-cise Exercise-induced changes in plasma concentration of IL-6 sIL-6R adrenaline noradrenaline cortisol and BDNF are reported in Figure 4 For IL-6 there was a main effect of time (F = 841 P lt 00001 η2 = 09) but no effect of condition (F = 12 P = 03 η2 = 005 Fig 4A) IL-6 was significantly elevated immediately after the constant load portion of all ex-ercise trials (P = 0027 mean difference 017 pgmiddotmLminus1 95 CI 0018ndash032 pgmiddotmLminus1) continued to increase after the time trial (P lt 00001 mean difference 040 pgmiddotmLminus1 95 CI 0032ndash049 pgmiddotmLminus1) and remained elevated 30 min after ces-sation of the exercise IL-6 concentration at rest was positively correlated with the mean RPE during the constant load portion of the exercise (P = 003 r = 04 95 CI 004ndash067) but was negatively related to the mean V O2 achieved during maximal exercise (P = 0029 r = minus041 95 CI minus067 to minus005) and distance traveled during maximal exercise (P = 0035 r = minus039 95 CI minus066 to minus001) In contrast distance cycled

FIGURE 4mdashPlasma IL-6 (A) sIL-6R (B) adrenaline (C) noradrenaline (D) cortisol (E) and BDNF (F) responses to exercise after three different sleep conditions aSignificantly different from PRE bSignificantly different from DUR cSignificantly different from POST dSignificantly different from 30 MIN

914 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

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was positively related to postexercise adrenaline concentration (P = 0038 r = 039 95 CI 0023ndash066)

The change in IL-6 from CON accounted for 25 of the variance in the mean V O2 achieved during maximal exercise and 22 of the distance cycled sIL-6R showed a main effect of time (F = 58 P = 0005 η2 = 046) with no main effect of condition (F = 16 P = 023 η2 = 019) There was a trend for elevated sIL-6R after the time trial and 30 MIN however neither reached statistical significance (P = 011 and P = 008 respec-tively Fig 4B) sIL-6R concentration at rest was negatively cor-related with the mean RPE during the constant load portion of the exercise (P = 0009 r = minus049 95 CI minus073 to minus014) Adren-aline showed a significant main effect of time (F = 149 P lt 00001 η2 = 015) with no main effect of condition (F = 04 P = 067 η2 = 003 Fig 4C) Adrenaline was signif-icantly increased at each time point compared with rest peaking immediately after the time trial (P = 0001 mean dif-ference 072 ngmiddotmLminus1 95 CI 04ndash10 ngmiddotmLminus1) Noradren-aline showed a significant main effect of time (F = 307 P lt 00001 η2 = 039) with no main effect of condition (F = 06 P = 05 η2 = 001 Fig 4D) Post hoc tests revealed that noradrenaline was increased from rest at each time point peaking immediately after time trial (P lt 00001 mean differ-ence 22 ngmiddotmLminus1 95 CI 15ndash28 ngmiddotmLminus1) The resting concentration of noradrenaline was negatively correlated with the mean RPE during the constant load portion of the exercise (P = 004 r = minus046 95 CI minus075 to minus002) BDNF showed a significant main effect of time (F = 232 P lt 00001 η2 = 022) with no effect of condition (F = 002 P = 098 η2 = 0008) BDNF was significantly elevated at each time point after exercise peaking immediately after time trial (P = 0002 mean difference 3090 pgmiddotmLminus1 95 CI 1210ndash4970 pgmiddotmLminus1) Cortisol displayed significant main ef-fects of time (F = 62 P = 0002 η2 = 041) and condition (F = 38 P = 004 η2 = 029 Fig 4E) However after a correc-tion for multiple comparisons there were no clear patterns to the variation of the data Cortisol concentration at rest was posi-tively correlated with the mean RPE during the constant load portion of the exercise (P = 0002 r = 056 95 CI 024ndash077)

DISCUSSION

This study investigated the role of selected cytokine and neuroendocrine factors in altered physiological and perceptual responses to exercise after partial and complete sleep depriva-tion A single night of sleep deprivation led to an increased perception of fatigue impaired maximal exercise performance decreased blood glucose elevated IL-6 at rest and a reduction in physical activity in the 12 h after sleep deprivation This increase in IL-6 may be mediated in part by altered glucose homeostasis Neither partial nor complete sleep deprivation altered cytokine or neuroendocrine responses to exercise However perception of effort was significantly increased after 24 h of sleep deprivation which was also associated with var-iations in the resting plasma concentrations of IL-6 sIL-6R cortisol and noradrenaline Maximal exercise performance

was impaired likely through an increased perception of ef-fort which may be mediated in part by an increase in resting IL-6 concentration (Fig 2A) With the exception of subjective fatigue and resting blood glucose partial sleep deprivation had minimal effects on the responses measured in the current study however these findings should not be extrapolated to scenarios of chronic partial sleep deprivation Taken together these findings provide novel insights into the mechanisms that may contribute to an increased perception of effort and ulti-mately impaired exercise performance after sleep deprivation

In accordance with previous studies we have demonstrated that perception of effort but not physiological responses to in-tensity matched submaximal exercise was affected by sleep deprivation and that subsequent maximal aerobic exercise performance was impaired and coincided with significantly lower physiological responses (Fig 3A) (32223) These re-sponses were also preceded by disruptions in mood and partic-ularly subjective perception of fatigue (Table 1) which have routinely been observed in the context of impaired sleep (9) Interestingly subjective fatigue before exercise and perception of effort during the submaximal exercise were both related to the mean V O2 and distance cycled during maximal exercise providing further evidence of their importance in exercise per-formance Importantly sleep deprivationndashinduced elevations in IL-6 were associated with an increased perception of effort during exercise and exercise performance and the mean V O2

achieved during maximal exercise Perhaps the most convinc-ing evidence from the current study is that 22 of the variance in performance between conditions was accounted for by the change in resting IL-6 between conditions Notably when we examined the IL-6 response to exercise there was no rela-tionship to performance or the detrimental effects of sleep dep-rivation this seems to be yet another example of the subtle and context-dependent nature of IL-6 signaling This is a signifi-cant result given the highly complex and multifactorial nature of exercise performance As such it seems that IL-6 may play a role in impaired exercise performance after sleep depriva-tion potentially mediated via an increased perception of effort Previous studies have shown that sleep deprivationndashinduced increases in IL-6 are associated with an increased perception of pain (24) Given the link between perception of effort and pain perception it is highly plausible that the two phenomena may be linked or interact It is feasible that perceived effort is increased in part by the pain-sensitizing effect of IL-6 how-ever this is somewhat speculative and further work is re-quired to investigate the potentially subtle role of IL-6 in mediating these responses Furthermore we demonstrated that resting blood glucose was lowered after both partial and com-plete sleep deprivation (Fig 2B) which was positively related to the increase in IL-6 (Fig 2C) Given the established role of IL-6 in glucose metabolism (25) it is highly plausible that al-terations in glucose metabolism are partly responsible for the increase in IL-6 The source of the increased plasma IL-6 after sleep deprivation remains poorly understood however it is feasible that skeletal muscle may be the source of additional IL-6 in this context given that IL-6 production by skeletal

APPLIED

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muscle is influenced by muscle glycogen content (26) which has been shown to be reduced after sleep deprivation (27)

With the exception of the aforementioned results for IL-6 the effects of sleep deprivation on sIL-6R and neuroendocrine factors measured in the current study were minimal Contrary to findings from a recent epidemiological study (11) we found that the plasma concentration of BDNF was not reduced after sleep deprivation but that lower concentrations of BDNF were related to negative changes in mood As such it is possible that sleep deprivation per se is not the direct cause of reduced BDNF reported in insomnia suffers or those with impaired sleep and it is more likely that the accumulated psychological stress as-sociated with insomnia results in decreased BDNF (7) Sleep deprivation had no discernible effect on sIL-6R and this find-ing is interesting considering the extremely limited and some-what conflicting available evidence regarding the effect of sleep on sIL-6R Dimitrov and colleagues (28) previously re-ported that sleep deprivation abolished the sleep-induced in-crease in sIL-6R whereas in a longitudinal setting our group previously reported that sIL-6R was positively related to subjectively reported sleep quality (15) Interestingly recent evidence suggests that the relationship may be bidirectional in that sleep can also be affected by IL-6 trans-signaling through sIL-6Rndashmediated responses within the brain (29) this com-plex interaction warrants further research in those with chronic sleep conditions

We found a main effect of sleep condition on plasma corti-sol which accounted for 29 of the variance in the resting values with cortisol appearing higher after both partial and complete sleep deprivation (Fig 4E) however post hoc com-parisons were not statistically significant This seems some-what reflective of previous studies as the effect of sleep deprivation on cortisol remain largely unclear with studies having reported no effect (30) increased (31) and decreased (32) plasma cortisol concentration However in the current study we observed a positive relationship between resting cor-tisol concentration and RPE (r = 056) which is very similar to the correlation reported (r = 0551) in a previous longitudinal study that assessed the relationship between cortisol and ses-sion RPE (33) As such cortisol responses to sleep deprivation remain unclear but our results further emphasize the role of cortisol in effort perception

Similarly we found no effect of sleep condition on the rest-ing concentration of adrenaline or noradrenaline which does appear in accordance with the apparent consensus (34) How-ever resting adrenaline concentration was negatively related to perception of fatigue at rest whereas postexercise adrenaline concentration was positively related to exercise performance These findings would appear in line with the established role of adrenaline in facilitating physical activity but highlight the importance of subjective fatigue in this relationship

Similarly to IL-6 resting cortisol concentration was posi-tively correlated with perception of effort during exercise Taken together it may be that although adrenaline noradrenaline and cortisol are not affected by sleep deprivation per se they do play a role in alterations of mood and effort perception

during exercise Furthermore it seems that differences in exercise-induced adrenaline concentration also account for some variation in performance This is important when consid-ering recent evidence that individual differences in anxiety and psychological stress play a role in immune responses to exercise (35) Any interactions between sleep mood and immunendash endocrine responses are likely to be complex and interdepen-dent and future studies should be carefully designed to examine potential interactions and investigate the direction of effects

It is well documented that sleep and physical activity share a bidirectional relationship (36) and can also be involved in de-velopment of chronic health conditions such as diabetes or obesity (37) In this regard we found that free-living energy expenditure was reduced in the 12 h after sleep deprivation and was negatively related to the level of subjective fatigue re-ported by participants in the morning before exercise It may be that an increased perception of fatigue as a result of im-paired sleep may make exercise a less attractive prospect therefore resulting in reduced levels of physical activity If re-peated this could have important negative consequences for long-term health However it is important to stress that the current study examined responses to single-night sleep depri-vation and although this is similar to the quantity of sleep oc-casionally experienced by athletes before competition (2) or the sleep deprivation experienced by night shift workers (38) it is not necessarily representative of more prolonged sleep dep-rivation or chronic partial sleep deprivation Given the increased prevalence of sleep deprivation and physical inactivity in modern society this is an important finding and highlights the importance of subjective fatigue in the context of physical activity Physical activity levels were not significantly differ-ent in the 24-h period the day after the trial suggesting that physical activity levels return to normal after one complete sleep cycle As such it is important to emphasize that the cur-rent study focused specifically on acute sleep disturbance and that these findings should not be extrapolated to circumstances of chronic partial sleep deprivation which may indeed be a more common scenario In this regard future studies are re-quired to further investigate chronic partial sleep loss

In the current study exercise-induced changes in cytokine and neuroendocrine factors were largely maintained after par-tial and complete sleep deprivation This is important consider-ing that exercise-induced changes in IL-6 and BDNF (among a range of other factors) seem important for exercise-induced ad-aptations in insulin sensitivity lipolysis (3940) and improved cognition and mood status (41) Furthermore there is evidence from animal studies that chronic exercise training can negate the increase in circulating IL-6 which is induced by sleep deprivation (42) suggesting that exercise training may in fact prevent some of the negative effects of sleep deprivation via anti-inflammatory mechanisms It is also possible that exercise-induced elevations in BDNF may help to mitigate some of the deleterious effects that sleep deprivation can have on mood status and perceived well-being It is important to emphasize that the effects observed in our study are likely multifactorial and highly complex and as such there are undoubtedly a wide

916 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

range of additional signaling factors that may also contribute to the observed responses In this regard we encourage fur-ther study to further explain variations in perceived fatigue and mood disturbance as a better mechanistic understanding may well lead to improved management of or countermea-sures to sleep deprivation

In conclusion the current study shows that elevated circu-lating concentrations of IL-6 at rest seem to play a role in the well-established impairments in mood perception of effort and exercise performance experienced after sleep deprivation In contrast cortisol adrenaline noradrenaline and BDNF were not affected by sleep deprivation but do seem to account for subtle variations in mood and effort perception Neither partial nor 24 h of sleep deprivation affects the cytokine and neuroendocrine responses to exercise measured in this study Furthermore we found that free-living energy expenditure was reduced after 24 h of sleep deprivation and that the level

REFERENCES 1 Goel N Basner M Rao H Dinges DF Circadian rhythms sleep dep-

rivation and human performance Prog Mol Biol Transl Sci 2013 119155ndash90

2 Fullagar HH Skorski S Duffield R Hammes D Coutts AJ Meyer T Sleep and athletic performance the effects of sleep loss on exercise performance and physiological and cognitive responses to exercise Sport Med 201545(2)161ndash86

3 Oliver SJ Costa RJ Laing SJ Bilzon JL Walsh NP One night of sleep deprivation decreases treadmill endurance performance Eur J Appl Physiol 2009107(2)155ndash61

4 Engle-Friedman M Mathew GM Martinova A Armstrong F Konstantinov V The role of sleep deprivation and fatigue in the per-ception of task difficulty and use of heuristics Sleep Sci 201811(2) 74ndash84

5 Proschinger S Freese J Neuroimmunological and neuroenergetic as-pects in exercise-induced fatigue Exerc Immunol Rev 2019258ndash19

6 Pollmaumlcher T Haack M Schuld A Reichenberg A Yirmiya R Low levels of circulating inflammatory cytokinesmdashdo they affect human brain functions Brain Behav Immun 200216(5)525ndash32

7 Giese M Unternaehrer E Brand S Calabrese P Holsboer-Trachsler E Eckert A The interplay of stress and sleep impacts BDNF level PLoS One 20138(10)e76050

8 Main LC Dawson B Heel K Grove JR Landers GJ Goodman C Relationship between inflammatory cytokines and self-report mea-sures of training overload Res Sports Med 201018(2)127ndash39

9 Pilcher JJ Huffcutt AI Effects of sleep deprivation on performance a meta-analysis Sleep 199619(4)318ndash26

10 Keramidas ME Gadefors M Nilsson L-O Eiken O Physiological and psychological determinants of whole-body endurance exercise following short-term sustained operations with partial sleep depriva-tion Eur J Appl Physiol 2018 Jul 23118(7)1373ndash84

11 Schmitt K Holsboer-Trachsler E Eckert A BDNF in sleep insom-nia and sleep deprivation Ann Med 201648(1ndash2)42ndash51

12 Shearer WT Reuben JM Mullington JM et al Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight J Allergy Clin Immunol 2001 107(1)165ndash70

13 Vargas NT Marino F A neuroinflammatory model for acute fatigue during exercise Sports Med 201444(11)1479ndash87

14 Robson-Ansley P Cockburn E Walshe I Stevenson E Nimmo M The effect of exercise on plasma soluble IL-6 receptor concentration a dichotomous response Exerc Immunol Rev 20101656ndash76

of subjective fatigue at rest explained a significant proportion of the variance Taken together these findings highlight the importance of IL-6 in the perception of effort and fatigue which is an important finding given the increasing prevalence of sleep deprivation and physical inactivity in modern society

The authors would like to wholeheartedly thank the participants for their considerable efforts throughout the study They would also like to thank Dr Matthew Cook and Karolis Kvasas for their assistance with data collection The results of the study are presented clearly honestly and without fabrication falsification or inappropriate data manipula-tion The results of the study do not constitute endorsement by the American College of Sports Medicine

This research did not receive any specific grant from funding agen-cies in the public commercial or not-for-profit sectors This research was supported by the National Institute for Health Research Leicester Biomedical Research Centre The views expressed are those of the au-thors and not necessarily those of the NHS the National Institute for Health Research or the Department of Health

The authors report no conflicts of interest in this work

15 Cullen T Thomas AW Webb R Phillips T Hughes MG sIL-6R is related to weekly training mileage and psychological well-being in athletes Med Sci Sports Exerc 201749(6)1176ndash83

16 Buysse DJ Reynolds CF Monk TH Berman SR Kupfer DJ The Pittsburgh Sleep Quality Index a new instrument for psychiatric practice and research Psychiatry Res 198928(2)193ndash213

17 Brage S Brage N Franks PW Ekelund U Wareham NJ Reliability and validity of the combined heart rate and movement sensor Actiheart Eur J Clin Nutr 200559(4)561ndash70

18 Curran SL Andrykowski MA Studts JL Short Form of the Profile of Mood States (POMS-SF) psychometric information Psychol Assess 19957(1)80ndash3

19 McLean BD Coutts AJ Kelly V McGuigan MR Cormack SJ Neuromuscular endocrine and perceptual fatigue responses during different length between-match microcycles in professional rugby league players Int J Sports Physiol Perform 20105(3)367ndash83

20 Borg G Hassmeacuten P Lagerstroumlm M Perceived exertion related to heart rate and blood lactate during arm and leg exercise Eur J Appl Physiol Occup Physiol 198756(6)679ndash85

21 Dill DB Costill DL Calculation of percentage changes in volumes of blood plasma and red cells in dehydration J Appl Physiol 197437(2)247ndash8

22 Myles WS Sleep deprivation physical fatigue and the perception of exercise intensity Med Sci Sports Exerc 198517(5)580ndash4

23 Temesi J Arnal PJ Davranche K et al Does central fatigue explain reduced cycling after complete sleep deprivation Med Sci Sports Exerc 201345(12)2243ndash53

24 Haack M Sanchez E Mullington JM Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers Sleep 200730(9) 1145ndash52

25 Glund S Deshmukh A Long YC et al Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle Diabetes 2007 56(6)1630ndash7

26 Steensberg A Febbraio MA Osada T et al Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content J Physiol 2001537(Pt 2)633ndash9

27 Skein M Duffield R Edge J Short MJ Mundel T Intermittent-sprint performance and muscle glycogen after 30 h of sleep deprivation Med Sci Sports Exerc 201143(7)1301ndash11

28 Dimitrov S Lange T Benedict C et al Sleep enhances IL-6 trans-signaling in humans FASEB J 200620(12)2174ndash6

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29 Oyanedel CN Kelemen E Scheller J Born J Rose-John S Peripheral and central blockade of interleukin-6 trans-signaling differentially af-fects sleep architecture Brain Behav Immun 201550178ndash85

30 Dimitrov S Lange T Tieken S Fehm HL Born J Sleep associated regulation of T helper 1T helper 2 cytokine balance in humans Brain Behav Immun 200418(4)341ndash8

31 Spiegel K Leproult R Van Cauter E Impact of sleep debt on meta-bolic and endocrine function Lancet 1999354(9188)1435ndash9

32 Vgontzas AN Mastorakos G Bixler EO Kales A Gold PW Chrousos GP Sleep deprivation effects on the activity of the hypothalamicndashpituitaryndashadrenal and growth axes potential clinical implications Clin Endocrinol (Oxf ) 199951(2)205ndash15

33 Balsalobre-Fernańdez C Tejero-Gonzaĺez CM Del Campo-Vecino J Relationships between training load salivary cortisol responses and performance during season training in middle and long distance runners PLoS One 20149(8)e106066

34 Mullington JM Haack M Toth M Serrador JM Meier-Ewert HK Cardiovascular inflammatory and metabolic consequences of sleep deprivation Prog Cardiovasc Dis 200951(4)294ndash302

35 Edwards JP Walsh NP Diment PC Roberts R Anxiety and per-ceived psychological stress play an important role in the immune response after exercise Exerc Immunol Rev 20182426ndash34

36 Kline CE The bidirectional relationship between exercise and sleep implications for exercise adherence and sleep improvement Am J Lifestyle Med 20148(6)375ndash9

37 Knutson KL Spiegel K Penev P Van Cauter E The metabolic consequences of sleep deprivation Sleep Med Rev 200711(3) 163ndash78

38 Valliegraveres A Azaiez A Moreau V LeBlanc M Morin CM Insomnia in shift work Sleep Med 201415(12)1440ndash8

39 Wedell-Neergaard AS Lang Lehrskov L Christensen RH et al Exercise-induced changes in visceral adipose tissue mass are regu-lated by IL-6 signaling a randomized controlled trial Cell Metab 201929(4)844ndash55

40 Pedersen BK Febbraio MA Muscles exercise and obesity skel-etal muscle as a secretory organ Nat Rev Endocrinol 20128(8) 457ndash65

41 Pietrelli A Matković L Vacotto M Lopez-Costa JJ Basso N Brusco A Aerobic exercise upregulates the BDNFndashserotonin systems and improves the cognitive function in rats Neurobiol Learn Mem 2018155528ndash42

42 Chennaoui M Gomez-Merino D Drogou C et al Effects of exercise on brain and peripheral inflammatory biomarkers induced by total sleep deprivation in rats J Inflamm (Lond) 201512(1)56

918 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg

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29 Oyanedel CN Kelemen E Scheller J Born J Rose-John S Peripheral and central blockade of interleukin-6 trans-signaling differentially af-fects sleep architecture Brain Behav Immun 201550178ndash85

30 Dimitrov S Lange T Tieken S Fehm HL Born J Sleep associated regulation of T helper 1T helper 2 cytokine balance in humans Brain Behav Immun 200418(4)341ndash8

31 Spiegel K Leproult R Van Cauter E Impact of sleep debt on meta-bolic and endocrine function Lancet 1999354(9188)1435ndash9

32 Vgontzas AN Mastorakos G Bixler EO Kales A Gold PW Chrousos GP Sleep deprivation effects on the activity of the hypothalamicndashpituitaryndashadrenal and growth axes potential clinical implications Clin Endocrinol (Oxf ) 199951(2)205ndash15

33 Balsalobre-Fernańdez C Tejero-Gonzaĺez CM Del Campo-Vecino J Relationships between training load salivary cortisol responses and performance during season training in middle and long distance runners PLoS One 20149(8)e106066

34 Mullington JM Haack M Toth M Serrador JM Meier-Ewert HK Cardiovascular inflammatory and metabolic consequences of sleep deprivation Prog Cardiovasc Dis 200951(4)294ndash302

35 Edwards JP Walsh NP Diment PC Roberts R Anxiety and per-ceived psychological stress play an important role in the immune response after exercise Exerc Immunol Rev 20182426ndash34

36 Kline CE The bidirectional relationship between exercise and sleep implications for exercise adherence and sleep improvement Am J Lifestyle Med 20148(6)375ndash9

37 Knutson KL Spiegel K Penev P Van Cauter E The metabolic consequences of sleep deprivation Sleep Med Rev 200711(3) 163ndash78

38 Valliegraveres A Azaiez A Moreau V LeBlanc M Morin CM Insomnia in shift work Sleep Med 201415(12)1440ndash8

39 Wedell-Neergaard AS Lang Lehrskov L Christensen RH et al Exercise-induced changes in visceral adipose tissue mass are regu-lated by IL-6 signaling a randomized controlled trial Cell Metab 201929(4)844ndash55

40 Pedersen BK Febbraio MA Muscles exercise and obesity skel-etal muscle as a secretory organ Nat Rev Endocrinol 20128(8) 457ndash65

41 Pietrelli A Matković L Vacotto M Lopez-Costa JJ Basso N Brusco A Aerobic exercise upregulates the BDNFndashserotonin systems and improves the cognitive function in rats Neurobiol Learn Mem 2018155528ndash42

42 Chennaoui M Gomez-Merino D Drogou C et al Effects of exercise on brain and peripheral inflammatory biomarkers induced by total sleep deprivation in rats J Inflamm (Lond) 201512(1)56

918 Official Journal of the American College of Sports Medicine httpwwwacsm-msseorg